Process for the preparation of enteric medicaments

ABSTRACT

An improved enteric coating for medicament less soluble in gastric juice or water is obtained by coating a medicament with an organic solvent-soluble cellulose derivative in which the hydrogen atom of one hydroxyl group has been substituted by a carboxymethyl group and at least one of other hydroxyl groups have been esterified or etherified.

United States Patent 1191 1111 3,789,1 17 Tsujino Jan. 29, 1974 PROCESSFOR THE PREPARATION OF 1 OTHER PUBLICATIONS ENTERIC MEDICAMENTS Ott etal., Cellulose and Cellulose Derivatives, 2nd [75] Inventor: TakulchlTSllJlIlO, Tokyo, Japan Ed" p 1955 pages 1451 14 0 [73] Assignee: Freund Ind. C0., Ltd., Tokyo, Japan Primary Examiner-Shep K. Rose [22]Flled' July 1971 Attorney, Agent, or Firm-Richard C. Sughrue et al. [21]Appl. No.: 164,115 1 5 7] ABSTRACT 52 US. Cl 424/35, 117/166, 260/226,An improved enterie coating for medicament less 2 0 231 A, 424 94 ublein gastric juice or water is obtained by coating a 5 Int CL 01 17 00 3441 3 30g 3 00 medicament with an organic solvent-soluble cellulose 58]Field Of Search ..424/35; 117/166; derivative in which t y g atom of one2 Q/ 2 1 droxyl group has been substituted by a carboxymethyl group andat least one of other hydroxyl groups have References Cited beenesterified or etherified.

UNITED STATES PATENTS 7 Claims, N0 Drawings 3,629,237 12/1971 Koyanagiet al. 1. 260/226 PROCESS FOR THE PREPARATION OF ENTERIC MEDICAMENTSBACKGROUND OF THE INVENTION The present invention relates to a processfor the preparation of enteric medicaments and more particularly to aprocess for the preparation of enteric medicaments less soluble ingastric juice or water by using a specific organic solvent-solublecellulose derivative.

DESCRIPTION OF THE PRIOR ART As a process for producing entericmedicaments, there is known a process in which medicaments are coatedwith a dibasic acid monoester derivative such as cellulose acetatephthalate'or cellulose acetate succinate. By using such a cellulosederivative, a beautiful enteric coating can be quite readily obtained byemploying an ordinary pan coating method or a fluidization process.However, when such a cellulose derivative is used for preparing entericcoating for some kinds of enzymes such as pancreatins, bromelin,trypsin, chymotrypsin, and the like, it sometimes happens that theenteric property of the coated medicament is lost with the passage oftime during preservation. Furthermore, it is known that such entericmedicament is insolublized in artificial enteric juice of thepharmacopoeia or becomes soluble in artificial gastric juice. Theseproblems are also described in the article Recent PharmaceuticalTechniques in Nippon Yakugyo Shinbun (Japan Pharmaceutical News) ofSept. 27, 1969.

This is believed to be cuased by the fact that the free carboxyl groupof the cellulose derivative (e. g., phthalic acid when the cellulosederivative is cellulose acetate phthalate) is decomposed by an esteraseor a medicament having a faculty of hydrolyzing it since the bond of thecarboxyl group is by the ester linkage.

On the other hand, processes of producing medicaments by using thecopolymers of unsaturated carboxylic acids or esters thereof, vinylacetate, styrene, etc., are disclosed in Japanese Patent PublicationNos. Sho 37-11843, Sho 44-11916, and Sho 44-22834. However, since such acopolymer having vinyl bond has high tackiness and hence there is atendency of causing sticking of tablets or stripping of coating duringthe coating operation, pin holes are readily formed and also it isdifficult to form a sufficient coating. Such troubles by the tackinessare also described in Film coating (2) for tablet; in Yakkyoku(Pharmacy); Vol. 17, No. 7.

SUMMARY OF, THE INVENTION Therefore, an object of this invention is toprovide a novel process of preparing enteric medicaments withoutaccompanied with such troubles in conventional manners.

The object of this invention. is attained by using, as the entericcoating material, an organic solvent-soluble cellulose derivative inwhich the hydrogen atom of a hydroxyl group has been substituted by acarboxymethyl group and at least one of the remaining hydroxyl groupshave been esterified or etherified. The substitution degree of thecarboxymethyl group in the cellulose derivative used in this inventionis 0.3-l.2 per anhydrous glucose unit.

DETAILED DESCRIPTION OF THE INVENTION The cellulose derivative used inthis invention may also be shown by the general formula wherein R and Reach represents a hydrogen atom or an esterified or etherified group, atleast one of said R and R however, must be an esterified or etherifiedgroup.

Examples of the ester group include an acetic acid ester group, apropionic acid ester group, a butyric acid ester group, a nitric acidester group, a higher fatty acid group, and the like and examples of theether group include an alkyl ether group, a hydroxyalkyl ether group,and the like. The cellulose derivative of this invention has one or moresuch ester groups or ether groups as the substituents.

The practical examples of the cellulose derivative of this invention arecarboxymethyl cellulose acetate, carboxymethyl hydroxypropyl celluloseacetate, carboxymethyl ethyl cellulose, and the like. Furthermore, forthe purpose of providing plasticity and humidity resistance to theenteric medicaments, higher fatty acid ester derivatives such ascarboxymethylcellulose stearic acid ester derivative are preferablyused.

An enteric medicament is usually prepared by dissolving an entericcoating material in an organic solvent and coating a medicament with thesolution. That is, the esterification or etherification by theintroduction of groups R and R is for solublizing the cellulosederivative in organic solvents and then the cellulose derivatives ofthis invention include the ester and ether derivatives of cellulose. Inparticular, the esterification gives no bad influences on the stabilityof the enteric medicament prepared.

The relations of the substitution rate of the carboxymethyl group incarboxymethyl cellulose acetate which is one of the cellulosederivatives in this invention and the solubilities of the carboxymethylcellulose acetate in water, artificial gastric juice, and artificialenteric juice are shown in Table 1.

TABLE 1 Substitution Artificial Artificial rate Water gastric juiceenteric juice 0 insoluble insoluble insoluble 0.1 do. do. do. 0.2 do.do. slightly swelled 0.3 do. do. collapsed 0.4 do. do. do. 0.5 do. do.dissolved I do. do. do. 1.0 do. do. do. l.l do. do. do. l.2 do. do. do.1 3 slightly do. do.

swelled l.4 swelled slightl do.

swelled 1.5 do. swelled do.

The coating materials used in this invention are readily dissolved inmethanol, ethanol, isopropanol, ethyl acetate, benzene, toluene,dioxane, acetone, methylene chloride, trichloroethylene,trichloroethane, chloroform, etc., alone or a combination of them toprovide clean and suitable coating material solutions having ethylcellulose is the substitution degree of the carboxymethyl group.

EXAMPLE 1 a: Carboxymethyl cellulose acetate (0.7) parts Ethyl cellulose1 part Butylphthalybutyl glycolate 0.5 part Titanium oxide suitableamount 1 l acetone-ethanol mixture to make 100 parts While stirring1,000 g. of tablets each having a diameter of 9.0 mm. and a weight of250 mg. and containing 200 mg. of bromelin in a rotary coating pan, thecoating solution having the above composition was uniformly applied tothe tablets and then the tablets are dried by air. By repeating theabove procedure, coating of 150 microns in thickness was formed and thusthe enteric medicament tablets having sufficient coatings were obtained.

b: Cellulose acetate phthalate (Pharmacopoeia grade) 10 parts Ethylcellulose 1 part Butylphthalybutyl glycolate 0.5 part Titanium oxidesuitable amount I l acetone-ethanol mixture to make 100 parts them inthe states of 45C. and 50 percent'or 80 percent in relative humidity.The results are shown in Table 2, in which the time when the coating wascol-- lapsed in artificial gastric juice or artificial enteric juice areshown in minute.

TABLE 2 Relative humidity 50% Relative humidity 80% lday 180 7days 18014days... 180 21days... l80 28days... 180

(A): Period of time when the medicaments were placed under theabove-said conditions; (B): Tablet coated by the solution (2) containingcarboxymethyl cellulose acetate; (B): Tablets coated by the solution (b)containing cellulose acetate phthalate; (1): ln artificial gastricjuice; and (2): ln artificial enteric juice.

EXAMPLE 2 The solution having the following composition was applied totablets each having a diameter of 10 mm. and a weight of 360 mg. andcontaining 300 mg. of pancreation as in Example 1 to form an entericcoating of 150 microns in thickness on the tablet.

Carboxymethyl ethyl cellulose (1.0) 10 parts Ethyl cellulose 1 partPolyethylene glycol 6000 0.5 part Tartrazine suitable amount 1 lacetone-isopropanol mixture to make 100 parts When the coatedmedicaments were subjected to the collapse test of the JapanPharmacopoeia, it was confirmed that the coated medicaments were stableand were not collapsed after 3 hours in gastric juice but were collapsedwithin 5 minutes in artificial enteric juice.

Furthermore, when they were placed for 30 days in the states of 45C. andpercent in relative humidity and then subjected to the collapse test asin Example 1, they were stable and were not collapsed after placed inartificial gastric juice for 3 hours but were collapsed within 5 minutesin artificial enteric juice.

What is claimed is:

1. A process for the preparation of an enteric medicament, whichcomprises coating a medicament with an organic solvent solution of anorganic solventsoluble cellulose derivative of the formula:

wherein at least one of said R and R must be a carboxy acid ester group,or an alkyl ether, or a hydroxy alkyl ether group, and the other one ofsaid R and R is a hydrogen atom,

the hydrogen atom of the hydroxyl group on the cellulose molecule beingsubstituted with a carboxy methyl group having a degree of substitutionranging from 0.3 to 1.2 per anhydrous glucose unit.

2. The processof claim 1, wherein said cellulose derivative is a memberselected-from the group consisting of carboxymethyl, cellulose acetate,carboxymethyl hydroxypropyl cellulose acetate, carboxymethyl ethylcellulose, and carboxymethyl cellulose stearic acid ester derivatives.

3. The process of claim 1, wherein said organic solvent is a memberselected from the group consisting of methanol, ethanol, isopropanol,ethyl acetate, benzene, toluene, dioxane, acetone, methylene chloride,trichloroethylene, and chloroform.

4. The process of claim 1, wherein said medicament to be coated is anenzyme.

5. The process of claim 1, wherein the ester so formed is a memberselected from the group consisting of an acetic acid ester group, apropionic acid ester group, a butyric acid ester group, and a higherfatty acid group.

6. The process of claim 1, wherein a nitric acid ester group replacessaid carboxy acid ester group.

7. An enteric coated medicament prepared by the process of claim 1.

2. The process of claim 1, wherein said cellulose derivative is a memberselected from the group consisting of carboxymethyl, cellulose acetate,carboxymethyl hydroxypropyl cellulose acetate, carboxymethyl ethylcellulose, and carboxymethyl cellulose stearic acid ester derivatives.3. The process of claim 1, wherein said organic solvent is a memberselected from the group consisting of methanol, ethanol, isopropanol,ethyl acetate, benzene, toluene, dioxane, acetone, methylene chloride,trichloroethylene, and chloroform.
 4. The process of claim 1, whereinsaid medicament to be coated is an enzyme.
 5. The process of claim 1,wherein the ester so formed is a member selected from the groupconsisting of an acetic acid ester group, a propionic acid ester group,a butyric acid ester group, and a higher fatty acid group.
 6. Theprocess of claim 1, wherein a nitric acid ester group replaces saidcarboxy acid ester group.
 7. An enteric coated medicament prepared bythe process of claim